Short periods (<=20min.d -1) of extremely low magnitude (<<10 microstrain), high frequency (15-90 Hz) mechanical stimuli (LMMS) introduced non-invasively into the skeleton augment both the quantity and quality of trabecular bone. Following one year of loading, femoral condyles from adult sheep realize a 10.5% increase in trabecular volume fraction, a 12% increase in longitudinal stiffness and a 27% increase in strength. Early work on humans shows potential that this biomechanical modality may serve as an intervention to prevent, and even reverse osteoporosis. As promising as LMMS may be in treating this crippling disease, the biological and physical mechanisms whereby these signals are effective has not been addressed. Three specific aims will be used to better understand the mechanisms by which these low-level signals are anabolic: 1. To begin identifying those genes involved in the anabolic response, adult female mice responsive to LMMS (C57BL/6J) will be subject to daily LMMS treatment (10 min, 45 Hz, 0.3g). Early through late (1, 4, 10 & 21 d) patterns of expression of fifteen candidate genes, representing those involved in formation and resorption of bone, will be quantified and compared to alterations in bone remodeling and morphology, as well as to baseline and long-term control animals. 2. To help validate the role of these genes in regulating bone adaptation, adult female mice that are unresponsive to LMMS (C3H/HeJ) will be exposed to the signal and alterations in gene activity examined (as above). 3. To begin to address a physical mechanism whereby LMMS is anabolic in some, but not all, tissues, we will test the hypothesis that the osteocyte in the responsive mouse strain alters its own morphology and interaction with the lacunae in a manner distinct from osteocytes in the unresponsive strain. These studies will help define how the cell perceives and responds to subtle changes in its physical environment, and represents a critical step in establishing the mechanistic basis for a non-pharmacologic, non-invasive treatment for osteoporosis.